DK163512B - Substituted azacyclohexyl derivatives of rifamycins, and salts thereof, pharmaceutical preparations which comprise these compounds, and a process for preparing the compounds - Google Patents

Description

in

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The present invention relates to novel substituted azacyclohexyl derivatives of rifamycins of the formula CH3 CH3 CH3 R, O · H · CO · O · H · d · H · · · · · · · · · · · · · · Wherein CH is hydrogen or trialkylacetyl, R5 is hydrogen or acetyl, and R3 is alkyl, and its salts, their preparation and pharmaceutical preparations containing these compounds.

WO Publication No. 87/02361 discloses 10 rifamycin derivatives which structurally differ only from the compounds of formula I in that, instead of the oxazole ring, they contain the usual iminocarbonyl group -CO-NH- for rifamycin S and SV. These known compounds have potent antibiotic activity, whereas the compounds of formula I are surprisingly practically free of antibiotic action, as will become apparent in the following.

The numbering of the ring system used is similar to that used in e.g. U.S. Patent No. 4,005,077.

The compounds of formula I contain several chirality centers with the usual configurations for rifamycins.

The compounds of formula I may exist as salts, especially pharmaceutically useful salts. Since the compounds of the invention contain basic centers, they can form acid addition salts. These are formed, for example, with inorganic

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2 acids, such as mineral acids, e.g. sulfuric acid or a phosphorus or hydrogen halide acid, or with organic carboxylic acids, such as optionally, e.g. with halogen substituted C (1-4) -alkanecarboxylic acids, e.g. acetic acid, optionally unsaturated dicarboxylic acids, e.g. oxalic, malonic, amber, maleic, fumaric, phthalic or terephthalic, hydroxycarboxylic acids, e.g. glycolic, lactic, apple, vinyl citric, amino acids, e.g. aspartic or glutamic acid, or organic sulfonic acids such as optionally, e.g. with halogen, substituted C (1-4) -alkanoic or arylsulfonic acids, e.g. methane, bromobenzene or toluene sulfonic acid. Corresponding acid addition salts can also be formed with the additional basic center present.

Furthermore, the compounds of the invention with an acidic phenolic hydroxy group can form salts with bases, e.g. alkali metal salts such as sodium or potassium salts. The invention also includes salts of compounds of formula I which are not suitable for pharmaceutical use, such salts being useful, for example, for the isolation or purification of the subject compounds or their pharmaceutically useful salts.

In particular, trialkylacetyl means tri-C (1-7) -alkylacetyl, preferably tri-C (1-4) -alkyl-acetyl, where alkyl has the meaning given below. First of all, mention is made of pivaloyl.

Alkyl especially means C 1-7 alkyl and is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl and further comprises similar pentyl, hexyl and heptyl groups. C (1-4) alkyl, preferably methyl, is preferred.

It is known that rifamycin SV derived derivatives have pronounced antibiotic properties and can be used, for example, to treat tuberculosis. It is therefore very surprising that the compounds of formula I and

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3 their pharmaceutically useful salts in the conventional pharmacological test models do not exhibit any similar antibiotic activity, which has been experimentally verified.

Further, it is surprising that the compounds of this invention have a significant lipid-lowering effect, which can be demonstrated by animal experiments, preferably with mammals, e.g. rats. Thus, the lowering of "very low density", "low density" and "high density" lipoproteins (VLDL, LDL 10 and HDL) in serum can be detected by two experimental models, namely in male genetically hypercholesterolemic rats (model A) and normolipemic rats of both sexes (model B).

For example, in vitro testing for antibiotic efficacy is performed by determining the minimum inhibitory concentration of MIC in the conventional plate test. As microorganisms in the present case, in particular, Mycobacterium tuberculosis TB H37RV and Staphylococcus aureus are used. For compounds with lipid-lowering indication, an antibiotic effect is considered adverse as it can lead to antibiotic-resistant microorganism strains, especially with prolonged administration.

In the above-mentioned test methods, the compounds of the invention exhibit repeated administration in the dose range from ca. 1 to approx. 10 mg / kg / day a significant hypolipidemic effect. Unsurprisingly, the compounds of the invention show practically no antibiotic effect. For example, the minimum inhibitory concentration for various pathogenic Staphylococcus aureus strains is above 130 µg / ml. such concentrations are approx. 1000 times greater than the concentrations needed to achieve a similar effect when treated with modern standard antibiotics.

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4

Especially because of their LDL lowering effect, the compounds of the invention can be used e.g. as hypo-lipidemia for the treatment of hyperlipidemia, mainly of the type. Ila and Ilb, and atherosclerosis, e.g. in cases with hyperlipoproteinemia as a risk factor.

Accordingly, the compounds of formula I and their pharmaceutically useful salts can be used as pharmaceuticals, e.g. as hypolipidemics for the treatment of hyperlipidemia, mainly of type Ila and Ilb, and of arteriosclerosis in the case of hyperlipoproteinemia as a risk factor. The invention also relates to a pharmaceutical composition containing a compound of the invention, especially hypolipidemics and anti-arteriosclerotic drugs, which are used for therapeutic and prophylactic treatment. The industrial preparation of the active compounds of formula I is also encompassed by the invention.

The invention relates in particular to the compounds of formula I and their salts wherein R 1 is pivaloyl and R 3 is methyl.

The invention relates in particular to the novel compounds of formula I described in the Examples and their preparation.

The process according to the invention is characterized in that a) is reacted with a compound of the formula CH'3 CH3 CH3 2 \ / \ / \ / \ T * * * H3C ° '· Oh 6h 5 in CH3 i.,, / / \ (Ha) OR! 0- {NCH3 "" VW * (SO / x ~ y * 6 - in OH N.-.

ch3 no

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Wherein R 1 is hydrogen or trilavalkylacetyl, and R 2 is hydrogen or acetyl, or a salt thereof having a compound of the formula <pi3 · - · Z-CU 2 - R 3 (I Ib) Wherein H is reactively esterified hydroxy and R3 is alkyl, or b) to prepare compounds of formula I or salts thereof wherein R 1 is trialkylmethylcarbonyl and R 2 is acetyl, a compound of formula 9H3 <pi3 <ρ3 Rz is heated. ° \ / \ / \ / \ H «, ii« is \ 3 0} ° \, / VH (III) /? R, fEl L c »> YYSZ p.

uX X

ch3 Νϊ ch3 wherein R 1 is trialkylmethylcarbonyl R 2 is acetyl and R 3 is alkyl, or c) is heating or irradiating a compound of the formula <pi3 <fH3 <fH3 Rz ° \ / \ / \ / \ i L Jh i1 HS <V \ b . 0 S (/ R n 0 VNh, <iv) ά a Λ.-Αί, ij i1 ... Ϊ "! / YYX>« «= - <> -« = 0—- ·. 0 -! = · Ch3 wherein R 1 is trialkylcarbonyl, R 2 is acetyl, and R 3 is alkyl and, if desired,

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6 is a compound of formula I or a salt thereof prepared from another of the above processes into another compound of formula I or a salt thereof, or converting a free compound of formula I to a salt thereof by 5 or of the above processes prepared salt of a compound of formula I to the free compound of formula I or to another salt thereof.

Salts of the starting compounds of formulas Ila, III and IV, which contain an acidic phenolic hydroxy group, are salts with bases of the kind listed above, while corresponding starting compounds with basic centers can also form acid addition salts analogously to the compounds of formula I.

In particular, reactively esterified hydroxy is esterified hydroxy with a strong inorganic acid or organic sulfonic acid, for example halogen such as chlorine, bromine or iodine, sulfonyloxy such as hydroxysulfonyloxy, halogenesulfonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen, substituted C (1-7) alkanesulfonyloxy, e.g. methane or trifluoromethanesulfonyloxy, C (5-7) -cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally, e.g. with C (1-7) -alkyl or halogen, substituted benzenesulfonyl-oxy, e.g. p-bromobenzene or p-toluenesulfonyloxy.

The reactions described above and hereinafter are carried out in a manner known per se, in the absence or usually in the presence of a suitable solvent or diluent or in a mixture of solvents or diluents, working as required under cooling, at room temperature or under heating, e.g. in a temperature range of approx. -80 ° C up to the boiling point of the reaction medium, preferably from ca.

-10 ° C up to approx. 180 ° C and, if necessary, in a closed, pressurized container, in an inert gas atmosphere

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7 and / or under anhydrous conditions.

The work-up of the reaction product of formula I from the resulting reaction mixture is carried out in a manner known per se, e.g. by dilution with water and / or optionally by neutralization or weak acidification (to pH about 3) with an aqueous acid such as an inorganic or organic acid, e.g. a mineral acid, or advantageously, citric acid, and the addition of a water-immiscible solvent such as a chlorinated hydrocarbon, e.g. chloroform or methylene chloride, whereby the reaction product of formula I passes into the organic phase, from which it is customary, e.g. by drying, evaporation of the solvent and crystallization and / or chromatography of the residue or other conventional purification methods can be obtained in purified form.

Process a) Z is reactively esterified hydroxy, preferably halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as methane or p-toluenesulfonyloxy.

The reaction is carried out in a manner known per se, advantageously in the presence of a base.

Preferably, as bases, non-nucleophilic tertiary amines, e.g., trilavalkylamines, basic heterocyclic compounds, and carbocyclic amines such as ethyl diisopropylamine, triethylamine, pyridine, 1,5-diaza-bicyclo [4.3.0] non-5-ene ( DBN) and 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU).

Process b) The treatment of compounds of formula III is carried out under heating, e.g. in a temperature range of approx. 50

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8 to 180 ° C, especially from ca. 100 to 170 ° C.

The starting material of formula III can be prepared, for example, by reacting rifamycin S or 3-halo-, especially 3-bromo-, rifamycin S with an amine of formula <? H3 • - · t - f

Hn () n-CH2 - ζ V-R3 (IIIa) • - · is · h3 wherein R3 is alkyl.

The reaction is carried out especially in excess of amine of formula IIa, for example in a temperature range of approx. 0 to 10 approx. 100 ° C. A mixture of the quinone and hydroquinone forms is formed. This mixture can, by reduction, e.g. by catalytic hydrogenation, is converted to the corresponding hydroquinone (derivative of rifamycin SV) (Rx = H). When treated with similar acylating agents, e.g. with an acid anhydride, such as pivaloyl chloride, in the presence of a base such as pyridine, compounds of formula III wherein Rx is trialkylacetyl can be obtained.

Process c)

The reaction is carried out in particular in an organic solvent, e.g. an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or methyl ethyl ketone, a chlorinated hydrocarbon such as chloroform or trichloroethane, an ether such as diethyl ether, a base such as pyridine or triethylamine, or a nitrile such as acetonitrile . As the solvent, isopropanol and pyridine are preferably used.

If the temperature is too low, the reaction proceeds very slowly, while at too high temperatures large amounts of unwanted by-products are formed. A suitable temperature

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9 area is from approx. 50 to approx. 90 ° C, preferably approx. 75 ° C.

The radiation is carried out in a manner known per se, for example, using conventional radiation sources, such as microwave radiation.

The compound of formula I formed can be purified or isolated e.g. by chromatography and / or by recrystallization from a suitable solvent such as petroleum ether.

The starting material of formula IV can be prepared in a manner known per se, for example by reacting a compound of formula CH3 CH3 CH3

RzVVV \ ί Oh Oh · H3C0 \ / \ \

Y ch3 0 II

/ V \ h, (TVa) · '? H fl>

H3C \ / \ / \ / H

i II II ϊ * 3 fYYX-W \ _Rl o ·. Wherein R 2 is acetyl and R 3 is alkyl with an acylation reagent introducing the trialkylacetyl group at positions 8 and 14.

The introduction of the trialkylacetyl group can be carried out in a manner known per se using a suitable acylating agent, using at least two equivalents of the acylating agent. Thus, for example, a trialkylacetic acid may be used, if necessary in the presence of a suitable condensing agent such as dicyclohexylcarbodiimide, but preferably a reactive derivative of such an acid such as an anhydride, especially a mixed one, is used.

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Anhydride, e.g. with an inorganic acid, such as a hydrogen halide acid, especially hydrochloric acid or hydrobromic acid (ie, the corresponding acid halide, eg chloride), or with an organic acid such as (trifluoroacetic) acetic acid or a suitable carbonic acid ester optionally a symmetrical anhydride. The trialkylacetic acid derivative used as an acylating agent is preferably used in the presence of a basic agent. As suitable basic agents, a non-acylatable organic base such as a heteroaromatic base, e.g. pyridine, collidine or quinoline, or a tertiary amine, e.g. triethylamine, N-ethylpiperidine, N-methyl-morpholine or 1,4-dimethyl-piperazine or 1,5-diazobicyclo-[5.4.0] undec-5-ene.

The acylation is usually carried out in the presence of a solvent or diluent, as an excess of the acylating agent or base, e.g. pyridine, together with an acylating agent. Other 20 solvents which, for example, may also be mixed with a base, are e.g. non-acylatable organic solvents such as hydrocarbons, e.g. pentane, hexane or cyclohexane, halogenated hydrocarbons, e.g. methylene chloride or chloroform, ethers, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, acid esters such as ethyl acetate, and acid amides, e.g. acetamide or dimethylformamide.

The reaction is usually carried out at room temperature or slightly higher temperature, e.g. up to approx. 706C, the reaction being carried out if necessary under an inert gas atmosphere. The acylation conditions, in particular the amount of acylating agent, the reaction medium, the temperature and the reaction time, must be selected such that both acyl groups are introduced and for this purpose the methodology described in detail in the examples is preferably used. reaction

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The process can advantageously be followed by conventional analytical methods, particularly by thin layer chromatography.

The starting material of formula IVa is known or can be prepared in a manner known per se. In this connection, reference is made in particular to the previously mentioned WO Publication No. 87/02361.

A compound of formula I or a salt thereof according to the invention can be converted into another compound of formula I. known per se

Compounds of formula I wherein R 1 is hydrogen can be acylated in known manner, for example by reaction with a trialkyl acetic acid or a reactive derivative thereof. Such reactive derivatives are, for example, 15 anhydrides, including mixed anhydrides, such as an acid halide, e.g. an acid chloride, or anhydrides with a carbonic acid ester or activated carboxylic acid esters such as cyanmethyl, (4) -nitrophenyl, polyhalogenphenyl, e.g. pentachlorophenylester. The reaction with the trialkylacetic acid or a salt thereof is carried out under water decomposition conditions, e.g. during azeotropic removal of the water formed by the reaction, or by treatment with a suitable condensing agent, e.g. N, N'-dicyclohexylcarbodiimide. The reaction with a reactive trialkylacetic acid derivative is advantageously carried out in the presence of a base. Similarly, the acetyl group R 2 can be introduced into compounds of formula I wherein R 2 is hydrogen by treatment with a corresponding acetylating agent.

When treated with strong bases, such as alkali metal hydroxides, the acetyl group R 2 and the trialkyl acetyl group R 1 can be exchanged with hydrogen. The trialkylacetyl group R 1 can also be selectively cleaved in the presence of the acetyl group R 2, e.g. by treatment with a fluoride such as an alkali metal fluoride, e.g. sodium or cesium fluoride,

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12 or an ammonium fluoride, e.g. tetrabutylammoniumfluo chloride.

Salts of compounds of formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula I are obtained by reaction with an acid or a suitable ion exchange reagent.

Salts can be converted in the usual manner to the free compounds of formula I, acid addition salts, e.g. at reaction with a suitable basic agent.

Depending on the process or reaction conditions, the compounds of the invention with salt-forming, especially basic properties, can be obtained in free form or preferably in the form of salts.

The novel compounds of formula I, including their salts of salt-forming compounds, may also be obtained in the form of hydrates or containing other solvents used for the crystallization.

Depending on the choice of starting compounds and method 20, the novel compounds of formula I may be in the form of one of the possible isomers or as mixtures thereof, for example, depending on the number of asymmetric carbon atoms as pure optical isomers such as antipodes, or as isomer mixtures such as racemates, diastereoisomer mixtures or racemates mixtures.

Formed racemate mixtures, because of the physicochemical differences of the constituents, can be separated in known manner into the pure isomers or racemates, for example by fractional crystallization. 1

Furthermore, formed racemates can be separated in the known antipodes in known manner, for example by recrystallization from an optically active solvent, chromatography on

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13 chiral adsorbents, by suitable microorganisms, by cleavage with specific immobilized enzymes, over the formation of inclusion compounds, e.g. using chiral crown ethers, whereby only one enantiomer is complexed, or by conversion to diastereomeric salts, e.g. by reacting a basic end product tracemate with an optically active acid, e.g. a carboxylic acid such as tartaric or malic acid, or a sulfonic acid, e.g. camphorsulfonic acid, and separation of the diastereomeric mixture thus formed, for example due to the various solubilities of the constituents, in the diastereomers from which the desired enantiomer can be released by treatment with a suitable agent. Advantageously, the more active enantiomer is isolated.

The invention also relates to such embodiments of the process using the starting material of formula IIa in the form of a salt.

In the process according to the invention, preferably 20 such starting compounds are used which lead to the above-described particularly preferred compounds of formula I.

The compounds of formula I and their salts can be used alone or together with excipients as well as in combination with other active substances as a therapeutic agent, ie.

25 both curative and preventive treatment of diseases or disease-like conditions indicated or caused by e.g. an increased cholesterol and / or triglyceride content in the blood, especially in blood serum. The present active compounds are administered in therapeutically effective amounts, preferably in the form of pharmaceutical compositions together with conventional pharmaceutical carriers and / or adjuvants for warm blooded animals or, in particular, humans in need thereof. Depending on body weight, age and individual condition, daily doses corresponding to approx. 1 to approx. 100, especially

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14 approx. 3 to approx. 50 mg per kg of body weight, which in severe cases can be exceeded.

The invention further relates to pharmaceutical compositions containing the compounds of this invention or pharmaceutically useful salts thereof as active substances.

The present pharmaceutical compositions containing the subject compound or pharmaceutically useful salts thereof are enteral preparations such as oral or rectal administration, and parenteral administration to humans or warm blooded animals, the pharmacologically active substance occurring alone or in combination with a pharmaceutically useful carrier.

The present pharmaceutical compositions contain e.g.

15 from approx. 10 to approx. 80%, preferably from approx. 20 to approx.

60%, active compound of formula 1 or a pharmaceutically acceptable salt thereof. Pharmaceutical preparations for enteral or parenteral administration, for example, are those in dosage unit forms such as dragees, tablets, capsules 20 or suppositories, furthermore, ampoules. These are manufactured in a manner known per se, e.g. by conventional mixing, coating, dissolution or lyophilization methods. Thus, pharmaceutical preparations for oral administration can be prepared by combining the active substance with solid carriers, optionally granulating a formed mixture and processing the mixture or granulate, if desired or if necessary, after addition of suitable excipients, to tablets or dragee cores.

Suitable carriers are in particular fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; further, binders such as starch adhesives, using e.g. of maize, wheat, rice or potato

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, If desired, disintegrants, such as the starch species listed above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow agents, flow regulators and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragon cores are provided with suitable, if any, stomach-resistant coatings. uses concentrated sugar solutions optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastrointestinal cellulose acetate or cellulose ethyl acetate,

The tablets or dragee coatings may be added to dyes or pigments, e.g. for identifying or characterizing different doses of active substance.

Other pharmaceutical compositions for oral use are gelatin socket capsules, as well as soft, closed gelatin capsules and a plasticizer such as glycerol or sorbitol. The capsules may contain the active substance in the form of a granule, e.g. in admixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, as stabilizers may also be added. 1

For example, pharmaceutical compositions for rectal use are suppositories which consist of a combination of it

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16 active substance with a suppository matrix. As a suppository matrix, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols may be used. Furthermore, gelatin rectal capsules containing a combination of the active substance with matrix material can also be used. As a matrix material, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons may be used.

For parenteral administration, aqueous solutions of an active substance in water-soluble form, e.g. a water-soluble salt, further, suspensions of the active substance, such as similar oil injection suspensions, to which suitable lipophilic solvents or carriers such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, e.g. sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.

The dosage of a compound of formula I depends on the person or type of warm blood animal, the age and the individual condition as well as the mode of application. Usually an approximate daily dose of approx. 150 mg up to approx. 1500 mg divided into several equal doses by oral application to a human or warm-blooded animal with a body weight of approx. 75 kg.

The invention is further illustrated by the following examples.

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Example 1 17 30 g, 8-di-O-pivaloyl-3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -rifamycin SV is dissolved in the heat in 1000 ml of 5-methoxyethanol, and the solution is boiled under nitrogen for 5 hours at reflux. Then, the solvent is evaporated in vacuo and the residue is recrystallized twice from methanol. In this way, 8-O-pivaloyl-1-deoxy-15-dexoso-1,15-oxy-3- [4- (2,4,6-trimethylbenzyl) -piperazin-10-yl] -rifamycin is obtained with formula I wherein R 1 is pivaloyl, R 2 is acetyl and R 3 is methyl. Melting point: 160-165 ° C.

C56H73N3012, M = 979, found (MS): 979, 1 H-NMR (360 MHz, CDCl3, TMS): 1.49 (s, 9H, pivaloyl at 0-8).

0 CH3 CH3 CH3 H3C0 · · · 3 \ / \ / \ / \ # · · · h3co · d) H <!) H 5 • CH3 · Ri = Pivaloyl • · ^ 9Ri 9— {Χ ° η3 h3c, ί β Y il Y H3C \ ch3% h3c

The starting material can be prepared as follows:

A mixture of 5 g of 3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -rifamycin SV, 50 ml of dry pyridine and 4.5 ml of pivaloyl chloride is kept at 50 ° C for 30 minutes. Then, the solvent is evaporated in vacuo. The oily residue is dissolved in ethyl acetate and the solution is washed with 2N hydrochloric acid, with buffer solution of pH 7 and with sodium chloride solution. After drying with sodium sulfate and evaporation, the yellow residue is crystallized from

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18 ether / hexane. This gives 1,8-di-O-pivaloyl-3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -rifamycin SV, mp 203-204 ° C. CgiHHg ^Pig, M: 1081 (found 5 MS).

Example 2

To a solution of 10.7 g of the compound prepared in Example 1 above in 200 ml of tetrahydrofuran is added portionwise tetrabutylammonium fluoride trihydrate until the initial red color of the solution turns yellow. Then water is added, acidified with citric acid and the reaction product taken up in ethyl acetate. After washing the ethyl acetate extract with water and sodium chloride solution, it is dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from ether. This gives 1-deoxy-15-deoxo-1,15-oxy-3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -rif amycin of formula I wherein R hydrogen, R 2 is acetyl, and R 3 is methyl, in long lemon yellow prisms which are recrystallized from 20 methanol / water. Mp. 175®C.

c51h65n3 ° 11 'M: 895 (found MS, FD). UV spectrum in 0.01 N alcoholic HCl, maxima in nm / e: 241/37240, 298/23000, 330 (shoulder), 437/9920.

Q <pi3 <j! H3 γΗ3

HsC "N / \ / \ / \ • · ♦ ·

HaCO i h d> H · Y ch3 ·, • · / OH 0-ζ XCH3 H> VY s' \ h3cn._.

si) n-ch2- (ch3 o - {- CO OH · - · = · ch3 h3c

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Example 3 19

A solution of the compound prepared in Example 2 above in dioxane-1 N sodium hydroxide (1: 1) is left at room temperature for 21 hours. Then, the solution is diluted with water and acidified with citric acid and the reaction product is taken up in ethyl acetate and crystallized from ethyl acetate / ether. This gives 25-desacetyl-3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -1-deoxy-15-desoxo-1,15-oxy-rifamycin of formula I wherein R 2 represents hydrogen and R 3 is methyl, in the form of yellow crystals, m.p. 190-195 ° C (dec.). c49h63n3 ° 10 'M: 853 (found MS, FD).

9H3 fH3 fHj H0 \ / \ / \ / \ • · · · h3co i ώ Oh · '

1 CH * II

# · ^ OH 0- • Z '

HaVVY

o-J-CO OH · - ·, * - · ch3 h3c 'Example 4

To a solution of the compound prepared in Example 3 above in pyridine was added 10 equivalents of pivaloyl chloride and the mixture was allowed to stand at room temperature until no starting material was found in the reaction product by thin layer chromatography. The solution is rapidly evaporated in high vacuum to dryness, the residue is taken up in methylene chloride, the methylene chloride extract is washed with citric acid solution, buffer solution of pH 7 and saturated sodium chloride solution

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20 order. After drying and evaporation of the methylene chloride extract, a red residue is obtained which consists of 25-desacetyl-8-O-pivaloyl-3- [4- (2,4,6-trimethylbenzyl) -5-piperazin-1-yl] -1 -desoxy-15-desoxo-1,15-oxy-rifamycin of formula I wherein pivaloyl, R 2 is hydrogen, and R 3 is methyl.

c54h71n3 ° 11 'M: 937 (found MS, FD). 1 H-NMR (CDCl 3, 360 MHz): signal for the pivaloyl group at 1.41 (s, 9H, CH 3 C).

fH, 9H3 p3 H0 \ / \ / \ / \ t · · · h3co id) H άΐί · N. CH3 · I IJ Ri = Pivaloyl S ORi 0- / XCH3 fVVxW-r) · - 0 - CO OH · Χ · = · ch3 h3c ^

Example 5 4 g of 8-O, N-dipivaloyl-3- [4- (2,4,6-trimethylbenzyl) -piperazin-1-yl] -rifamycin S (prepared as described in WO87 / 02361, Example 1) are heated under protection from 15 candles in 70 ml of isopropanol in a pressure tube for 4 hours to 100 ° C. Then, the solvent is removed in vacuo and the dark red residue is chromatographed on 600 g of silica gel (Merck) with petroleum ether / ethyl acetate (3: 2). The substances contained in the first two zones are discarded. The following red fraction then contains the compound prepared in Example 1 above. Further product located on the chromatography column is eluted with ethyl acetate / methanol (9: 1) and purified again by further chromatography. After evaporation of the eluate, the 8-O-pivaloyl-1-dexoxy-15-deoxo-1,15-oxy-3- [4- (2,4,6-trimethylbenzyl) -piperazine-1] characterized in Example 1 is obtained. -yl] -rifamycin.

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Example 6 21

Capsules containing 250 mg of active compound of formula I, e.g. the compound of formula I wherein 5 is pivaloyl, R 2 is acetyl and R 3 is methyl can be prepared as follows:

Composition (for 1000 capsules):

Compound of Formula I 250.0 g

Corn starch 50.0 g Polyvinylpyrrolidone 15.0 g

Magnesium stearate 5.0 g

Ethanol q.s.

The compound of formula I is mixed with the corn starch and the mixture is moistened with a solution of polyvinylpyrrolidone 15 in 50 g of ethanol. The moist mass is pressed through a sieve with a mesh width of 3 mm and the granulate is dried at 45 ° C.

The dry granulate is sieved through a sieve with a mesh width of 1 mm and then mixed with 5 g of magnesium stearate. The mixture is filled into 0.320 g portions in 20 size 0 capsules.

Similarly, the other compounds prepared in the examples can also be used as active components.

EXAMPLE 7 250 g of active compound of Formula I according to one of Examples 1-5 and 1750 g of finely grated suppository matrix (eg cocoa butter) are thoroughly mixed and then melted. Of the melt, which is kept homogeneous by stirring, 1000 suppositories are cast of 2 g. Each suppository 30 contains 250 mg of active substance.

Example 8

DK 163512B

22

As experimental animals, albino rats weighing 180-240 g are used, namely the Spraque Dawley progeny of the COBS strain 5, which has free access to standard rat feed and drinking water. The test compound of formula I is orally administered in a 3% corn starch solution to groups of 8-10 rats daily for 5 consecutive days. The animals are sacrificed 2 hours after the last administration by stinging the heart and flow of 10 blood under anesthesia with carbon dioxide. 1 16 hours before the time of death, the animals are no longer fed. The total cholesterol, lipoprotein and triglyceride blood plasma levels are tuned separately for each test animal. To determine the lipoproteins, the VLDL and LDL fractions are precipitated in 1 ml of ethylenediaminetetraacetic acid against coagulation protected plasma by the addition of 200 units of heparin and of manganese chloride to a final concentration of 46 mmol / l and the fractions isolated by centrifugation. The supernatant is mixed with the remaining plasma and the enzymatic determination of the cholesterol and triglyceride content is carried out by e.g. the test systems of Sigma Chemical Co. (St. Louis, MO, USA).

Prior to the start of the experiment, the average cholesterol content was 69.4 mg / 100 ml plasma. The percent reduction in plasma cholesterol content caused by the test compounds of formula I is shown in the table below.

Compound Dose Reduction according to No. mg / kg% 1 10 46 30 1 30 60 2 30 70 4 10 38

Claims (9)

1. Substituted azacyclohexyl derivatives of rifamycin having the formula <pH3 fH3 <p «3 R <* 0 · · · * · S / \ / \ / \ ♦ · · * h3co y ba i) h · in CHs II} Λ ( I> • 7 OR! O— {\ h3 / \ A / * „ii U ... ίϋ! F'YY'x y ™ * - · ') -rb 0 - v OH · - · · = · CH3 N> CH 3 wherein R 1 is hydrogen or trialkylacetyl, R 2 is hydrogen or acetyl, and R 3 is alkyl, and salts thereof. A compound according to claim 1, characterized in that R 1 represents tri-C (1-7) -alkyl-acetyl, especially tri-C (1-4) -alkyl-acetyl, and R 3 means C (1-7) -alkyl, especially C (1-4) -alkyl. A compound according to claim 1, characterized in that R 1 is pivaloyl and R 3 is methyl. A compound according to claim 1, characterized in that R 1 is pivaloyl, R 2 is acetyl, and R 3 is methyl. A compound according to claim 1, characterized in that R 1 is pivaloyl, R 2 is hydrogen and R 3 is methyl. A compound according to any one of claims 1-5, characterized in that it is in the form of a pharmaceutically useful salt. DK 163512B 24 A compound according to any one of claims 1-6 for use as a hypolipidemic and anti-sclerotic drug. Pharmaceutical composition, characterized in that it contains as an active substance a compound according to any one of claims 1-5 in free form or in the form of a pharmaceutically useful salt. Process for the preparation of a compound according to any one of claims 1-5, characterized in that a (a) is reacted with a compound of the formula CH3 CH3 CH3 R2 ° \ / \ / \ / \ «« · · H3C0 J \ \ Y CH3 jj} Å (IIa) ·· QRi O - s ch3 H | V \ A /, Y (Y \> Ah, wherein R 1 is hydrogen or trialkylacetyl and R 2 is hydrogen or acetyl, or a salt thereof with a compound of Formula 9H3 z_CH1 - / - V-r3 <IIb> * = t £ h3 wherein Z is reactively esterified hydroxy and R3 is alkyl, or b) to prepare compounds of formula I or salts thereof wherein Rj is trialkylmethylcarbonyl, and R 2 represents acetyl, heats a compound of the formula DK-163512B 9H3 fH3? H3 Rz \ / \ / \ / \ -i Jh Ϊη · H3co · \ Ϊ c «3 0 II / Vnch, (III) <. ? * f * ICHl 'Y Y Y UXiX> K> Åh3 Ό Åh3 wherein trialkylmethylcarbonyl, R2 means acetyl / and R3 means alkyl, or c) heats or irradiates a compound of formula CH3 CH3 CH3 RgO. · · * 2 \ / \ / \ / \ • · · · «Oh Oh · 'HsC0 \ AYI CH3 n ϋ V \ A (IV) γνγχ> · - <>' CH3 X) Åh3 wherein R ^ means trialkylmethylcarbonyl, R £ is acetyl and R3 is alkyl, where desired converting a compound of formula I or a salt thereof into another compound of formula I or a salt thereof, or, if desired, one of the above processes prepared free compound of formula I into a salt thereof or converts a salt prepared by one of the above methods of a compound of formula I into the free compound of formula I or to another salt thereof.